Classical alkylating agents as well as the nitrosoureas evidently produce their therapeutic, as well as their mutagenic and carcinogenic effects by attacking the DNA of target cells. Therapeutic properties are probably related to the agent's ability to produce crosslinks in the DNA, and resistence may develop in cells that can repair this damage. The chemical nature of such crosslinks will be identified in this project, and means will be sought to produce structural changes which are resistant to repair. Synthetic polynucleosides can be studied separately. Since these polymers are effectively replicated by RNA polymerase, modified and unmodified polymers can be compared to determine which reactions are biologically significant. By obtaining data on different classes of agents - for example, classical alkylating agents in comparison with nitrosoureas - we will look for explanations of the clinically observed differences among these agents. Using information obtained on the kinds of modifications produced by different classes of agents, new compounds which combine some of the features of each class will be synthesized and tested for their antitumor activity.